Brain injury resulting from ischemic insults such as stroke, post-traumatic lesions and a variety of neurological disorders frequently causes significant neuro-degeneration resulting in mild to severe impairment and even death to those suffering from these injuries. Current treatment methods are limited and are typically related to invasive surgical procedures and post-injury rehabilitative treatments rather than limiting or reversing the damage caused by the initial injury to the brain.
Various studies implicate excitotoxic glutamate receptor activation in neuro-degeneration following ischemic insults, post-traumatic lesions and a range of other neurological disorders (Lipton and Rosenberg 1994; Arundine and Tymianski 2004). In pathological conditions excessive release of the neurotransmitter glutamate leads to activation of NMDA-subtype of glutamate receptors that triggers a deleterious cascade of intracellular events including Ca2+ overload and activation of effector molecules like p38 mitogen activated protein kinase (p38 MAPK) that is known to be involved in excitotoxic cell death (Barone et al. 2001a; Barone et al. 2001b). Recent findings suggest the existence of two functionally distinct pools of NMDA receptors (NMDAR) defined by the presence of NR2A (NR2A-NMDAR) or NR2B (NR2B-NMDAR) containing subunits (Luo et al. 1997; Tovar and Westbrook 1999; Kohr 2006). NR2B-NMDARs are generally thought to be involved in triggering cell death and subsequent brain damage following an excitotoxic insult (Liu et al. 2007; Tu et al. 2010). However pharmaceutical application of NR2B-NMDAR antagonists have been unsuccessful in clinical trials, since they interfere with physiological functions of these receptors, in addition to blocking excitotoxic cascades (Rodrigues et al. 2001; Zhao et al. 2005; Walker and Davis 2008).
Accordingly, targeting components of the intracellular signaling cascades downstream of NMDAR signaling may provide novel compounds for therapeutic approaches to interventions in excitotoxicity.
The brain-enriched tyrosine phosphatase STEP (also known as STriatal Enriched Phosphatase or PTPN5) may be one such target molecule that is activated following stimulation of NMDARs and is emerging as an important regulator of neuronal survival and death. STEP is expressed specifically in neurons of the striatum, neo-cortex and hippocampus (Boulanger et al. 1995). STEP61 and STEP46, the two STEP isoforms (Bult et al. 1997) contain a highly conserved substrate-binding domain termed as the kinase interacting motif or KIM domain (Pulido et al. 1998). Phosphorylation of a critical serine residue within the KIM domain is mediated through dopamine/D1 receptor dependent activation of the Protein Kinase A (PKA) pathway (Paul et al. 2000). Dephosphorylation of this residue by Ca2+ dependent phosphatase calcineurin, following glutamate/NMDA receptor stimulation, renders STEP active in terms of its ability to bind to its substrates (Paul et al. 2003). Active STEP, in turn can bind to and modulate the activity of its substrate through tyrosine dephosphorylation of a regulatory tyrosine residue. Known substrates of STEP include ERK (extracellular regulated kinase 1/2) and p38 MAPKs (Paul et al. 2007, Poddar et al., 2010, Xu et al., 2009), Src family tyrosine kinases and NMDAR subunits (Nguyen et al., 2002; Braithwaite et al., 2006), all of which are involved in neuronal survival and death.